Background/outlineThe paradigm that mutated genes cause cancer has become a guiding principle in my research since 1980. The effect of environmental factors in cancer causation is based on their mutagenic capability to alter cancer-prone genes leading to activation of oncogenes and elimination or silencing of tumor suppressor genes. The development of cancer from incipient malignant cells to invasive tumors and finally to metastases is driven by Darwinian expansion of clonal cell populations involving additional mutated cancer genes. Our research program began in 1987 and culminated in the identification in 1993 of the VHL TSG located at 3p25. In 1993-2003 we investigated the sequence structure of the VHL gene and identified and analyzed VHL target genes to discover the VHL pathway. In parallel we intensified research on mapping and molecular cloning of cancer genes located in 3p26, 3p21.3 and 3p12 involved in the origin and/or development of major forms of lung cancer and other common carcinomas of the kidney, breast and prostate. In 2000-2003 we investigated: (1) the methylation code of the VHL locus itself and the function of VHL target genes (carbonic anhydrases, CA9 and CA12, and the transcription regulator BHLHB2/STRA13); (2) continued deletion mapping in 3p21.3 by real time PCR in tumor tissues and cell lines and completed the isolation and initial characterization of candidate cancer-causing genes from both 3p21.3 regions (centromeric, LUCA, and telomeric, AP20). These 3p21.3 regions (centromeric, LUCA, and telomeric, AP20) should be considered contiguous cancer gene regions since each harbors clusters of candidate TSG. (3) We also identified candidate cancer genes in 3p26.3 and 3p12.3In 2003-2005 we focused our research on functional analysis (by finding interacting proteins, analyzing null mutants in mice, and bioinformatics annotations) of some of these candidate TSG. Cancer gene CALL (3p26)The gene, CALL on 3p26.3 encoding a trans-membrane cell adhesion molecule (CAM) capable of both homotypic and heterotypic binding, that we cloned in 1998 was shown to be involved in general cognitive activities (g/IQ) and some neurological diseases (i.e. schizophrenia).CALL is expressed in normal tissues beside the brain and is over-expressed in a variety of human tumors. A 3p26 genomic segment (containing two genes, CALL and CNTN6) was recently shown to harbor a candidate for prostate cancer susceptibility in Finish prostate cancer families although no mutations were detected in both residing genes. Our expression studies suggest that CALL may contribute to cancer invasive growth and metastasis (depending on stage it may act either as a "tumor suppressor" or "oncogene"). We hypothesize that during initial growth CALL is not expressed (silenced) in tumor cells to facilitate in situ tumor growth. Re-expression of CALL on the edge of the tumor mass could promote local invasive growth and furthermore allow tumor cells to enter and leave the blood stream, colonize distant tissues and establish metastatic tumors. Current work and plans: We are developing specific antibodies and will validate CALL as a biomarker of invasive tumor growth and metastasis and a novel target for immune intervention in leukemia, melanoma, and some lung and ovarian cancers over-expressing CALL.We also plan to analyze CALL for miRNA mutations in sporadic prostate and other cancers.VHL TSG (3p25)Aberrant methylation of CpG promoter islands of cancer genes is now accepted as a fundamental mechanism in carcinogenesis. Using the VHL locus as a model system, we investigated the mechanisms of aberrant DNA methylation in cancer. We also aimed to use epigenetic codes (CpG and histone codes) to understand whether they harbor variations associated with inter-individual differences that may determine risk of sporadic cancers.